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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Metformin: Is it Still the First Line in Type 2 Diabetes Management Algorithm?

Author(s): Maria Grammatiki, Rebecca Sagar and Ramzi A. Ajjan*

Volume 27, Issue 8, 2021

Published on: 22 December, 2020

Page: [1061 - 1067] Pages: 7

DOI: 10.2174/1381612826666201222154616

Price: $65

Abstract

Type 2 diabetes mellitus (T2DM) has an ever-growing prevalence worldwide, affecting 1 in 11 adults. It continues to significantly impact patients in terms of morbidity and mortality, in addition to impairing quality of life while adding to the spiralling healthcare costs. Metformin was first used over half a century ago, and for the past two decades, it has been considered first-line oral therapy to treat patients with T2DM, in whom lifestyle measures failed to improve glycaemic control. Early landmark studies supported a glycaemic benefit with metformin use with a relatively safe adverse effect profile, particularly with avoidance of hypoglycaemia. Moreover, studies have indicated other potential beneficial role for metformin on organs typically affected by diabetes complications. However, more recently, with the discovery of newer hypoglycaemic agents and the wealth of data provided by large-scale cardiovascular safety studies, algorithms for the treatment of patients with T2DM have become increasingly complex. Indeed, recent guidelines challenge current thinking and advocate the use of agents other than metformin as first-line agents in those with higher cardiovascular risk, potentially unseating metformin from its long-held throne. This narrative review aims to summarize the background and origins of metformin, assess its role in the current management of patients with T2DM, highlighting the clinical efficacy and safety profile of this agent. Also, the position of metformin in the clinical algorithms is discussed in light of the most recent evidence in the field, helping with an ever-increasing shift towards individualized patient care to maximize benefits and minimize risks.

Keywords: Metformin, diabetes, diabetes management, first-line therapy, T2DM, metformin.

[1]
International Diabetes Federation. IDF Diabetes Atlas. 9th ed. 2019. Available at: https://www.diabetesatlas.org
[2]
Bailey CJ. Metformin: historical overview. Diabetologia 2017; 60(9): 1566-76.
[http://dx.doi.org/10.1007/s00125-017-4318-z] [PMID: 28776081]
[3]
Pasik C. Diabetes and the biguanides: the mystery of each Glucophage: serving diabetology for 40 years. Lyon: Groupe Lipha 1997; p. 79.
[4]
International Diabetes Federation Clinical Guidelines Task Force. Global guideline for type 2 diabetes 2012. Available at: www.idf.org/e-library/guidelines/79-global-guideline-for-type-2-
[5]
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122(6): 253-70.
[http://dx.doi.org/10.1042/CS20110386] [PMID: 22117616]
[6]
Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994; 24(1): 49-57.
[http://dx.doi.org/10.3109/00498259409043220] [PMID: 8165821]
[7]
Gormsen LC, Sundelin EI, Jensen JB, et al. In vivo imaging of human 11C-metformin in peripheral organs: dosimetry, biodistribution, and kinetic analyses. J Nucl Med 2016; 57(12): 1920-6.
[http://dx.doi.org/10.2967/jnumed.116.177774] [PMID: 27469359]
[8]
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348(Pt 3): 607-14.
[http://dx.doi.org/10.1042/bj3480607] [PMID: 10839993]
[9]
Foretz M, Hébrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010; 120(7): 2355-69.
[http://dx.doi.org/10.1172/JCI40671] [PMID: 20577053]
[10]
Weijers RNM, Bekedam DJ. The Metformin Paradox. Curr Diabetes Rev 2020; 16(2): 143-7.
[http://dx.doi.org/10.2174/1573399814666181119145750] [PMID: 30451115]
[11]
Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334(9): 574-9.
[http://dx.doi.org/10.1056/NEJM199602293340906] [PMID: 8569826]
[12]
Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab 2003; 88(3): 1323-32.
[http://dx.doi.org/10.1210/jc.2002-021394] [PMID: 12629126]
[13]
Chen SC, Brooks R, Houskeeper J, et al. Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. Mol Cell Endocrinol 2017; 440: 57-68.
[http://dx.doi.org/10.1016/j.mce.2016.11.011] [PMID: 27856330]
[14]
Ford RJ, Fullerton MD, Pinkosky SL, et al. Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochem J 2015; 468(1): 125-32.
[http://dx.doi.org/10.1042/BJ20150125] [PMID: 25742316]
[15]
Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetol 2017; 60(9): 1577-85.
[http://dx.doi.org/10.1007/s00125-017-4342-z] [PMID: 28776086]
[16]
Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia 2011; 54(2): 339-49.
[http://dx.doi.org/10.1007/s00125-010-1937-z] [PMID: 20972533]
[17]
Bahne E, Sun EWL, Young RL, et al. Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. JCI Insight 2018; 3(23): 93936.
[http://dx.doi.org/10.1172/jci.insight.93936] [PMID: 30518693]
[18]
Preiss D, Dawed A, Welsh P, et al. DIRECT consortium group. Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes. Diabetes Obes Metab 2017; 19(3): 356-63.
[http://dx.doi.org/10.1111/dom.12826] [PMID: 27862873]
[19]
Lenhard JM, Croom DK, Minnick DT. Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments. Biochem Biophys Res Commun 2004; 324(1): 92-7.
[http://dx.doi.org/10.1016/j.bbrc.2004.09.021] [PMID: 15464987]
[20]
Lindsay JR, Duffy NA, McKillop AM, et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabet Med 2005; 22(5): 654-7.
[http://dx.doi.org/10.1111/j.1464-5491.2005.01461.x] [PMID: 15842525]
[21]
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352(9131): 854-65.
[http://dx.doi.org/10.1016/S0140-6736(98)07037-8] [PMID: 9742977]
[22]
Piera-Mardemootoo C, Lambert P, Faillie JL. Efficacy of metformin on glycemic control and weight in drug-naive type 2 diabetes mellitus patients: A systematic review and meta-analysis of placebo-controlled randomized trials. Therapie 2018.
[http://dx.doi.org/10.1016/j.therap.2018.01.006]
[23]
Bloomgarden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care 2006; 29(9): 2137-9.
[http://dx.doi.org/10.2337/dc06-1120] [PMID: 16936168]
[24]
Maloney A, Rosenstock J, Fonseca V. A Model-Based Meta-Analysis of 24 Antihyperglycemic Drugs for Type 2 Diabetes: Comparison of Treatment Effects at Therapeutic Doses. Clin Pharmacol Ther 2019; 105(5): 1213-23.
[http://dx.doi.org/10.1002/cpt.1307] [PMID: 30457671]
[25]
Hirst JA, Farmer AJ, Ali R, Roberts NW, Stevens RJ. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care 2012; 35(2): 446-54.
[http://dx.doi.org/10.2337/dc11-1465] [PMID: 22275444]
[26]
Lund SS, Tarnow L, Frandsen M, et al. Impact of metformin versus the prandial insulin secretagogue, repaglinide, on fasting and postprandial glucose and lipid responses in non-obese patients with type 2 diabetes. Eur J Endocrinol 2008; 158(1): 35-46.
[http://dx.doi.org/10.1530/EJE-07-0500] [PMID: 18166815]
[27]
Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes Care 2011; 34(Suppl. 2): S132-7.
[http://dx.doi.org/10.2337/dc11-s220] [PMID: 21525444]
[28]
International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 2019; 7(5): 385-96.
[http://dx.doi.org/10.1016/S2213-8587(18)30315-2] [PMID: 30926258]
[29]
Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355(23): 2427-43.
[http://dx.doi.org/10.1056/NEJMoa066224] [PMID: 17145742]
[30]
Wright AD, Cull CA, Macleod KM, Holman RR. UKPDS Group. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complications 2006; 20(6): 395-401.
[http://dx.doi.org/10.1016/j.jdiacomp.2005.08.010] [PMID: 17070446]
[31]
Inkster B, Zammitt NN, Frier BM. Drug-induced hypoglycaemia in type 2 diabetes. Expert Opin Drug Saf 2012; 11(4): 597-614.
[http://dx.doi.org/10.1517/14740338.2012.694424] [PMID: 22690846]
[32]
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15): 1577-89.
[http://dx.doi.org/10.1056/NEJMoa0806470] [PMID: 18784090]
[33]
DeFronzo RA, Goodman AM. The Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333(9): 541-9.
[http://dx.doi.org/10.1056/NEJM199508313330902] [PMID: 7623902]
[34]
Seifarth C, Schehler B, Schneider HJ. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes 2013; 121(1): 27-31.
[PMID: 23147210]
[35]
Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 2012; 35(4): 731-7.
[http://dx.doi.org/10.2337/dc11-1299] [PMID: 22442396]
[36]
Malin SK, Kashyap SR. Effects of metformin on weight loss: potential mechanisms. Curr Opin Endocrinol Diabetes Obes 2014; 21(5): 323-9.
[http://dx.doi.org/10.1097/MED.0000000000000095] [PMID: 25105996]
[37]
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356(24): 2457-71.
[http://dx.doi.org/10.1056/NEJMoa072761] [PMID: 17517853]
[38]
Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010; 170(14): 1191-201.
[http://dx.doi.org/10.1001/archinternmed.2010.207] [PMID: 20656674]
[39]
Paneni F, Lüscher TF. Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes. Am J Med 2017; 130(6S): S18-29.
[http://dx.doi.org/10.1016/j.amjmed.2017.04.008] [PMID: 28526186]
[40]
Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117-28.
[http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978]
[41]
Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER Steering Committee. LEADER Trial Investigators. Liraglutide and CV outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-22.
[http://dx.doi.org/10.1056/NEJMoa1603827] [PMID: 27295427]
[42]
Marso SP, Bain SC, Consoli A, et al. SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375(19): 1834-44.
[http://dx.doi.org/10.1056/NEJMoa1607141] [PMID: 27633186]
[43]
Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169(6): 616-25.
[http://dx.doi.org/10.1001/archinternmed.2009.20] [PMID: 19307526]
[44]
Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 2017; 60(9): 1620-9.
[http://dx.doi.org/10.1007/s00125-017-4337-9] [PMID: 28770324]
[45]
Eisenreich A, Leppert U. Update on the Protective Renal Effects of Metformin in Diabetic Nephropathy. Curr Med Chem 2017; 24(31): 3397-412.
[http://dx.doi.org/10.2174/0929867324666170404143102] [PMID: 28393693]
[46]
Polianskyte-Prause Z, Tolvanen TA, Lindfors S, et al. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. FASEB J 2019; 33(2): 2858-69.
[http://dx.doi.org/10.1096/fj.201800529RR] [PMID: 30321069]
[47]
Ravindran S, Kuruvilla V, Wilbur K, Munusamy S. Nephroprotective Effects of Metformin in Diabetic Nephropathy. J Cell Physiol 2017; 232(4): 731-42.
[http://dx.doi.org/10.1002/jcp.25598] [PMID: 27627216]
[48]
Kwon S, Kim YC, Park JY, et al. The long-term effects of metformin on patients with type 2 diabetic kidney disease. Diabetes Care 2020; 43(5): 948-55.
[http://dx.doi.org/10.2337/dc19-0936] [PMID: 32132005]
[49]
Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes Metab 2017; 19(4): 473-81.
[http://dx.doi.org/10.1111/dom.12854] [PMID: 27987248]
[50]
Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes 2015; 64(5): 1786-93.
[http://dx.doi.org/10.2337/db14-1388] [PMID: 25510240]
[51]
McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetol 2016; 59(3): 426-35.
[http://dx.doi.org/10.1007/s00125-015-3844-9] [PMID: 26780750]
[52]
Yang W, Cai X, Wu H, Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes 2019; 11(9): 729-43.
[http://dx.doi.org/10.1111/1753-0407.12900] [PMID: 30615306]
[53]
Masharani U, German M. Pancreatic hormones and diabetes mellitusGreenspan’s basic and clinical endocrinology. New York: Lange, McGraw-Hill Education 2017; p. 659.
[54]
Waters AK, Morgan DB, Wales JK. Blood lactate and pyruvate levels in diabetic patients treated with biguanides with and without sulphonylureas. Diabetologia 1978; 14(2): 95-8.
[http://dx.doi.org/10.1007/BF01263446] [PMID: 631461]
[55]
Féry F, Plat L, Balasse EO. Effects of metformin on the pathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patients. Metabolism 1997; 46(2): 227-33.
[http://dx.doi.org/10.1016/S0026-0495(97)90307-3] [PMID: 9030834]
[56]
DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism 2016; 65(2): 20-9.
[http://dx.doi.org/10.1016/j.metabol.2015.10.014] [PMID: 26773926]
[57]
Lazarus B, Wu A, Shin JI, et al. Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study. JAMA Intern Med 2018; 178(7): 903-10.
[http://dx.doi.org/10.1001/jamainternmed.2018.0292] [PMID: 29868840]
[58]
Peters N, Jay N, Barraud D, et al. Metformin-associated lactic acidosis in an intensive care unit. Crit Care 2008; 12(6): R149.
[http://dx.doi.org/10.1186/cc7137] [PMID: 19036140]
[59]
Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998; 338(4): 265-6.
[http://dx.doi.org/10.1056/NEJM199801223380415] [PMID: 9441244]
[60]
Eppenga WL, Lalmohamed A, Geerts AF, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 2014; 37(8): 2218-24.
[http://dx.doi.org/10.2337/dc13-3023] [PMID: 24842984]
[61]
U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kindey function Available at: http://www.fda.gov/Drugs/DrugSafety/ucm493 244.htm
[62]
Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41(12): 2669-701.
[http://dx.doi.org/10.2337/dci18-0033] [PMID: 30291106]
[63]
Cosentino F, Grant PJ, Aboyans V, et al. ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41(2): 255-323.
[http://dx.doi.org/10.1093/eurheartj/ehz486] [PMID: 31497854]
[64]
Neal B, Perkovic V, Mahaffey KW, et al. CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377(7): 644-57.
[http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]

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